6D8E

Discovery of a Highly Potent and Broadly Effective EGFR and HER2 Exon 20 Insertion Mutant Inhibitor

Summary for 6D8E

• Entry DOI: 10.2210/pdb6d8e/pdb
• Descriptor: Epidermal growth factor receptor, (4-fluorophenyl)methyl {2-[(1-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}[3-(propanoylamino)phenyl]carbamate (3 entities in total)
• Functional Keywords: egfr, inhibitor, signaling protein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 37793.63

Authors

Park, E.,Eck, M.J. (deposition date: 2018-04-26, release date: 2018-07-18, Last modification date: 2024-10-16)

Primary citation

Jang, J.,Son, J.,Park, E.,Kosaka, T.,Saxon, J.A.,De Clercq, D.J.H.,Choi, H.G.,Tanizaki, J.,Eck, M.J.,Janne, P.A.,Gray, N.S.
Discovery of a Highly Potent and Broadly Effective Epidermal Growth Factor Receptor and HER2 Exon 20 Insertion Mutant Inhibitor.
Angew. Chem. Int. Ed. Engl., 57:11629-11633, 2018

PubMed Abstract: Exon 20 insertion (Ex20Ins) mutations are the third most prevalent epidermal growth factor receptor (EGFR) activating mutation and the most prevalent HER2 mutation in non-small cell lung cancer (NSCLC). Novel therapeutics for the patients with Ex20Ins mutations are urgently needed, due to their poor responses to the currently approved EGFR and HER2 inhibitors. Here we report the discovery of highly potent and broadly effective EGFR and HER2 Ex20Ins mutant inhibitors. The co-crystal structure of compound 1 b in complex with wild type EGFR clearly revealed an additional hydrophobic interaction of 4-fluorobenzene ring within a deep hydrophobic pocket, which has not been widely exploited in the development of EGFR and HER2 inhibitors. As compared with afatinib, compound 1 a exhibited superior inhibition of proliferation and signaling pathways in Ba/F3 cells harboring either EGFR or HER2 Ex20Ins mutations, and in the EGFR P772_H773insPNP patient-derived lung cancer cell line DFCI127. Our study identifies promising strategies for development of EGFR and HER2 Ex20Ins mutant inhibitors.

PubMed: 29978938
DOI: 10.1002/anie.201805187

Experimental method

X-RAY DIFFRACTION (2.537 Å)